Project Summary: Diabetic Retinopathy (DR) disproportionately affects working age adults, minorities, and geriatric populations. It is the leading cause of blindness and quality of life deterioration worldwide. DR is characterized by inflammation, edema, and aberrant neovascularization in the posterior segment over the retina. Intraocular delivery of inhibitors of vascular growth have shown promise in preventing neovascularization in the retina. However, monthly injections leads to patient discomfort, potential endophthalmitis, and concerns about compliance and efficacy. The goal of this project is to decrease the number of annual injections from 12 to 2 (every 6 months) by using a hydrogel that is intrinsically anti-angiogenic and is able to sustain the long-term delivery of anti-angiogenic and anti-inflammatory drugs. Ultimately, we aim to demonstrate long-term attenuation of neovascularization and inflammation in the eye, potentially improving DR outcomes. The central hypothesis is that this hydrogel release system may provide sustained maintenance and treatment of neovascular posterior segment diseases, such as DR, over at least a 6 month period while laying the foundation for treatment of a myriad of neovascular and chronic inflammatory diseases. The technology proposed is based on a ?-sheet-based self-assembling peptide hydrogel (SAPH) to which biofunctional moieties can be attached. The functional anti-angiogenic sequences that will be tested are from known mimics of anti-angiogenic small molecules: Kringle (domain 5), laminin-1, and histidine-proline-rich glycoprotein. Preliminary data from Kringle-5 modified SAPH demonstrate robust anti- angiogenic activity of injectable hydrogels in vitro. We will continue analysis of this functional SAPH in vivo as we synthesize and characterize the other hydrogels. Further, we will encapsulate standard of care anti-VEGF antibody bevacizumab (mBev) and/or anti-inflammatory steroid triamcinolone acetonide (sTA) within anti- angiogenic hydrogels. Composite drug laden hydrogels will be assayed to uniquely or combinatorically treat DR. In a rodent DR model, we will investigate the sustained release of mBev and sTA, along with the anti-angiogenic hydrogels developed, in decreasing vascular leakage and aberrant vessel formation over a 6 month period. Further, a synthetic scheme, drug release kinetics, biocompatibility, immune response, and anti-angiogenic/anti- inflammatory activity in vitro and in vivo will be measures of incremental success in the project. Ultimately, we will aim to decrease the frequency of the injection schedule, leading to better patient compliance, lower risk of infection, and potentially long-term efficacy. Finally, this bimodal delivery system may prove useful for localized inhibition of vascularization and inflammation in neoplastic microenvironments, chronic inflammatory diseases, and others, especially where in situ site directed therapies are warranted.